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Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML

Overview of attention for article published in Clinical Cancer Research, May 2023
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  • Good Attention Score compared to outputs of the same age (73rd percentile)
  • Above-average Attention Score compared to outputs of the same age and source (56th percentile)

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Title
Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML
Published in
Clinical Cancer Research, May 2023
DOI 10.1158/1078-0432.ccr-22-3929
Pubmed ID
Authors

Christopher T. Letson, Maria E. Balasis, Hannah Newman, Moritz Binder, Alexis Vedder, Fumi Kinose, Markus Ball, Traci Kruer, Ariel Quintana, Terra L. Lasho, Christy M. Finke, Luciana L. Almada, Jennifer M. Grants, Guolin Zhang, Martin E. Fernandez-Zapico, Alexandre Gaspar-Maia, Jeffrey Lancet, Rami Komrokji, Eric Haura, David A. Sallman, Gary W. Reuther, Aly Karsan, Uwe Rix, Mrinal M. Patnaik, Eric Padron

Abstract

Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and PDX models of disease. We utilized standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data supports further clinical investigation of this combination.

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Attention Score in Context

This research output has an Altmetric Attention Score of 5. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 25 May 2023.
All research outputs
#6,682,990
of 23,842,189 outputs
Outputs from Clinical Cancer Research
#6,188
of 12,833 outputs
Outputs of similar age
#51,063
of 194,915 outputs
Outputs of similar age from Clinical Cancer Research
#39
of 87 outputs
Altmetric has tracked 23,842,189 research outputs across all sources so far. This one has received more attention than most of these and is in the 71st percentile.
So far Altmetric has tracked 12,833 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 11.3. This one has gotten more attention than average, scoring higher than 51% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 194,915 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 73% of its contemporaries.
We're also able to compare this research output to 87 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 56% of its contemporaries.